This phase II trial compares the effects, good and/or bad of abiraterone and prednisone or darolutamide alone in treating patients with prostate cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Androgens (male hormones) can cause the growth of prostate tumor cells. Abiraterone acetate lowers the amount of androgens made by the body. This may help stop the growth of prostate tumor cells that need androgen to grow. Darolutamide blocks the use of androgens by the tumor cells. Prednisone is used to lessen inflammation and lower the body's immune response. Researchers want to compare the side effects of standard of care (SOC) abiraterone and prednisone or darolutamide alone in treating patients with advanced prostate cancer.

PRIMARY OBJECTIVE:

I. Tolerability.

SECONDARY OBJECTIVES:

I. Tolerability in prespecified subpopulations.

II. Prostate-specific antigen (PSA) response at 7 months.

OUTLINE: Patients are assigned to 1 of 2 arms per treating physician preference.

ARM I: Patients receive abiraterone and prednisone per SOC. Treatment continues for 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples during screening and on study.

ARM II: Patients receive darolutamide per SOC. Treatment continues for 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples during screening and on study.

After completion of study intervention, patients are followed up for a total of 3 years.

Inclusion Criteria:

• Ability to understand and willingness to sign an informed consent form
• Histologically confirmed prostate adenocarcinoma
• Advanced prostate cancer appropriate for treatment with abiraterone acetate plus prednisone or darolutamide as assessed by the treating physician
• Participants are encouraged to be currently treated with androgen deprivation therapy (ADT) or having undergone bilateral orchiectomy
• Performance status 0 - 2 (Karnofsky ≥ 50%)
• Age ≥ 18 years at time of consent
• Life expectancy ≥ 6 months per investigator discretion
• Ability and stated willingness to adhere to the study visit schedule and other protocol procedures/requirements for the duration of the study

Exclusion Criteria:

• Have been on either abiraterone or darolutamide for > 28 days prior to initiating enrollment
• Any condition that in the opinion of the investigator would prohibit the understanding or rendering of informed consent or interfere with the participant's safety or compliance while on trial